Hydrocortisone controlled release formulation

ABSTRACT

The disclosure relates to a pharmaceutical formulation comprising hydrocortisone and its use in the treatment of conditions that would benefit from a delayed release of hydrocortisone, in particular conditions such as adrenal insufficiency, inflammatory conditions and depression.

FIELD OF THE INVENTION

The disclosure relates to a pharmaceutical formulation comprisinghydrocortisone and its use in the treatment of conditions that wouldbenefit from a controlled release of hydrocortisone, in particularconditions such as adrenal insufficiency, inflammatory conditions anddepression.

BACKGROUND TO THE INVENTION

In mammals the principle oscillator of circadian rhythms or centralclock is in the suprachiasmatic nucleus. This master oscillator isresponsible for the sleep-wake cycle and hormonal rhythms (e.g. cortisoland melatonin). It is recognised that peripheral tissues such as immunecells and the liver also have clock genes and their own molecularoscillating ability. Daily rhythms in gene expression, physiology andbehaviour persist under constant conditions and must, therefore, bedriven by self-sustained biological oscillators called circadian clocks.Circadian clocks can count time only approximately and must be adjustedevery day by the photoperiod in order to be in harmony with the outsideworld.

There is a desire to develop drug delivery means to provide controlleddrug release in particular in accordance with the circadian rhythm of apatient. There are a number of conditions that would benefit from thistreatment regimen, for example adrenal failure, primary, secondarytertiary adrenal insufficiency and steroid withdrawal, inflammatorydiseases such as rheumatoid arthritis and in the treatment of depressionand related depressive illnesses including chronic fatigue and myalgicencephalitis (ME).

Adrenal failure occurs in approximately 1/10,000 of the population. Itmay be due to either primary adrenal failure or secondary adrenalfailure (which occurs due to pituitary failure which may be caused by apituitary tumour or surgery). In primary adrenal failure, ACTH levelsfrom the pituitary will be high and in secondary adrenal failure ACTHlevels are inappropriately low. Administration of exogenousglucocorticoid or excessive secretion of endogenous glucocorticoid as inCushing's syndrome results in suppression of the hypothalamo-pituitaryadrenal (HPA) axis and occurs at all levels from the hypothalamus,pituitary and adrenal. This is referred to as tertiary adrenalinsufficiency.

This means that after excessive glucocorticoid exposure patients willhave low cortisol levels and suffer from either a temporary oroccasionally permanent cortisol deficiency (tertiary adrenalinsufficiency) which results in fatigue, weight loss and apredisposition to an adrenal crisis.

Long acting potent synthetic glucocorticoids such prednisolone anddexamethasone are more likely to cause adrenal suppression thanhydrocortisone. Hydrocortisone has the advantage of a short half-life(ca. 3 hours), is the native glucocorticoid, and can be given in lowdose. However, current preparations of hydrocortisone cannot reproducephysiological rhythms of cortisol. To maximise the recovery of the HPAthe glucocorticoid dose should not exceed the normal daily requirementand also allow initiation of the normal cortisol rhythm. If an immediaterelease glucocorticoid is given at night then it will generally preventthe night-time activation of the HPA axis. Suppression of the HPA axismay occur due to excessive treatment with exogenous glucocorticoids asin the treatment of inflammatory disorders such as rheumatoid arthritisand asthma. Similarly it is well recognised that Cushing's syndromeeither due to a pituitary or ectopic tumour producing ACTH or an adrenaltumour producing cortisol can result in adrenal suppression.

Inflammation is a complex reaction of the body responding to damage ofits cells and vascularised tissues. Inflammation can be acute orchronic. An acute inflammatory response is an immediate response by theimmune system to a harmful agent. The response includes vasculardilatation, endothelial and neutrophil cell activation. An acuteinflammatory response will either resolve or develop into chronicinflammation. Chronic inflammation is an inflammatory response ofprolonged duration, weeks, months, or even indefinitely, whose extendedtime course is provoked by the persistence of the causative stimulus toinflammation within the tissue. The inflammatory process inevitablycauses tissue damage. The exact nature, extent and time course ofchronic inflammation is variable, and depends on a balance between thecausative agent and the attempts of the body to remove it. Aetiologicalagents producing chronic inflammation include, but are not limited to:infectious organisms that can avoid or resist host defences and sopersist in the tissue for a prolonged period; infectious organisms thatare not innately resistant but persist in damaged regions where they areprotected from host defences; irritant non-living foreign material thatcannot be removed by enzymatic breakdown or phagocytosis; or where thestimuli is a “normal” tissue component, causing an auto-immune disease.

Glucocorticoids are commonly used for the treatment of inflammatorydiseases. A common side-effect is suppression of the endogenouscircadian rhythm of cortisol. The consequence is that patients may needweaning during withdrawal from glucocorticoids and during this weaningperiod they may have a flare of their disease or suffer from temporarycortisol deficiency that may provoke a flare in their disease.Suppression results from the provision of exogenous glucocorticoid thatacts to suppress the circadian rhythm of cortisol. This suppressiontakes place at all levels of the hypothalamo-pituitary-adrenal axis. Analternative treatment regimen is the use of steroids to treat theinflammatory condition. A steroid such as prednisolone is used to treatrheumatoid arthritis and is effective at reducing inflammation. Ifsteroids are used for extended periods their side effects includeosteoporosis, thinning of skin, weight gain and muscle wasting allfeatures of Cushing's syndrome. In addition the administration ofsteroids suppresses the endogenous circadian secretion of cortisol bythe adrenal glands and this has consequences for the patient who istreated with the steroid.

It is well recognised that depression is associated with loss of thenormal cortisol circadian rhythm. Similarly it is well recognised thatCushing's syndrome where a tumour results in loss of the circadianrhythm of cortisol causes depression [e.g. loss of circadian rhythmcauses disease]. Conditions which result in depression or a generalmalaise are well known. These include, but are not limited to, clinicaldepression, reactive depression, post-natal depression, depression whichresults as a consequence of extensive surgery, chronic fatigue, myalgicencephalitis and conditions such as jetlag. Depressive conditions canalso be induced by external effects which are self imposed, for exampledepression can result when a person is either dieting in an effort tolose weight or also when a person is attempting to treat an addiction,for example smoking or cocaine addiction. There are also less seriousconditions which result in general malaise, for example shift workerswho work unsociable hours can become tired and depressed due todisruption in their normal sleep pattern. It is also known that certainperiods of the year induce depression, for example Christmas andSeasonal Affective Disorder (SAD). The physiological effects ofdepression are varied. However, some general characteristics include,hyperactivity of the hypothalamo-pituitary-adrenal axis resulting inhigh cortisol levels, loss of the cortisol circadian rhythm and sleepdisturbance with early morning waking. High glucocorticoid levels atnight-time or at the time of going to sleep may also themselves disturbsleep.

In WO2003/015793 and WO2010/032006 we disclose pharmaceutical delayedand sustained formulations that deliver glucocorticoids in a delayed andsustained fashion in the control of adrenal insufficiency and otherconditions. This disclosure relates to the use of delayed releaseformulations which surprisingly can also be used in the treatment ofconditions that would benefit from the circadian delivery ofglucocorticoids such as hydrocortisone such as primary, secondary andtertiary adrenal insufficiency, inflammatory disease and conditions anddepression and depressive illnesses

STATEMENTS OF INVENTION

According to an aspect of the invention there is provided apharmaceutical composition adapted for oral administration comprising: acore comprising hydrocortisone and a carrier and contacting said core alayer comprising a delayed release polymer wherein said delayed releasepolymer is a pH sensitive enteric polymer and is adapted to delayrelease of hydrocortisone from said core.

According to an aspect of the invention there is provided apharmaceutical composition adapted for oral administration comprising: acore comprising hydrocortisone and a carrier and contacting said core alayer comprising a delayed release polymer wherein said delayed releasepolymer is a single or blend of pH sensitive enteric polymer(s) and isadapted to delay release of hydrocortisone from said core characterizedin that the core comprises microcrystalline cellulose which is 75-85%w/w of the composition.

Thus for a medication to replicate this rhythm, when taken last thing atnight between approximately 20:00 to 24:00 h, the medication wouldrequire a delay in release of 2 to 5 hours and a release to provide apeak level between 06:00 to 09:00 h and maintain cortisol levels above100 nmol/l until approximately 19:00 h. Naturally this medication couldbe taken earlier in the evening or later depending on the subjectsnormal sleep pattern and the rhythm would then be appropriately phaseadvanced or delayed.

In a preferred embodiment of the invention said carrier is a hydrophilicmolecule.

In a preferred embodiment of the invention said hydrophilic molecule orpolymer is selected from the group consisting of: mannitol, xylitol,sucrose or glucose.

Preferably said hydrophilic molecule is in the form of a sugar bead.

In an alternative preferred embodiment of the invention said carrier isa hydrophilic polymer.

In a preferred embodiment of the invention said hydrophilic polymer ishydroxypropylmethylcellulose or hydroxypropylethylcellulose.

In an alternative preferred embodiment of the invention said carrier isa hydrophobic polymer or small molecule.

Preferably said hydrophobic polymer is microcrystalline cellulose ordicalcium phosphate.

In a preferred embodiment of the invention said carrier comprisesmicrocrystalline cellulose particles wherein the diameter of saidparticles is between 200 μm to 1200 μm.

Preferably the diameter of said particles is 500 μm to 800 μm.

In a preferred embodiment of the invention said carrier comprises orconsists essentially of 75-85% w/w microcrystalline cellulose of thecomposition.

Preferably said carrier comprises 80-82% w/w microcrystalline cellulose;most preferably about 81% w/w microcrystalline cellulose of thecomposition.

In a preferred embodiment of the invention hydrocortisone is present inor on the said carrier between a concentration of 2-10% w/w of thecomposition.

More preferably the concentration of hydrocortisone in or on the saidcarrier is between a concentration of 5-8% w/w of the composition.

In a preferred embodiment of the invention the concentration ofhydrocortisone is about 6% w/w of the composition.

In a preferred embodiment of the invention hydrocortisone is present inor on the said carrier together with a binding agent such as povidone.

Preferably the concentration of povidone is between the concentration0.5-4% w/w of the composition.

More preferably the concentration of povidone is between theconcentration 1.5-3% w/w of the composition.

In a preferred embodiment of the invention povidone is provided at aconcentration of about 1.8% w/w of the composition.

In a preferred embodiment of the invention said delayed release layer isan enteric polymer wherein the dissolution of said composition isbetween pH 5.5 and 7.0; preferably between pH 6.0 and 6.8.

In a preferred embodiment of the invention said enteric polymer isselected from the group consisting of: acrylic and/or poly [methyl]acrylic polymers, cellulose acetate succinate or polyvinylacetatephathlate.

Preferably, said enteric polymer is a methacrylic acid derivative;preferably Eudragit L100 and/or Eudragit S100.

In a preferred embodiment of the invention said enteric polymer isEudragit S100.

In an alternative preferred embodiment of the invention said layerconsists essentially of a mixture of Eudragit S100 and Eudragit L100.

In a preferred embodiment of the invention the ratio of Eudragit S100and Eudragit L100 is about 4:1.

In a preferred embodiment of the invention said enteric polymer isprovided at between 5-10% w/w; preferably 6-8% w/w, most preferablyabout 7% w/w of the composition.

In a preferred embodiment of the invention said enteric polymer layercomprises a plasticiser such as dibutyl sebacate.

Preferably the dibutyl sebacate in said enteric polymer layer is presentbetween 0.5-1.0% w/w of the composition.

More preferably the dibutyl sebacate in said enteric polymer layer ispresent at about 0.7% w/w of the composition.

According to an aspect of the invention there is provided apharmaceutical composition adapted for oral administration comprising:

-   -   a core comprising hydrocortisone and a carrier;    -   a layer comprising a delayed release polymer contacting said        core wherein said delayed release polymer is a pH sensitive        enteric polymer which is a mixture of Eudragit L100 and Eudragit        S100 [1:4] at about 6-7% w/w of the composition, which is        adapted to delay release of hydrocortisone from said core.

In a preferred embodiment of the invention said composition consistsessentially of a core and delayed release layer as represented in Table1.

In a preferred embodiment of the invention said composition comprises1-30 mg per unit dose of hydrocortisone or cortisone acetate; preferablyabout 5, 10, 20, or 30 mg of hydrocortisone per unit dose.

In a preferred embodiment of the invention said composition iscompressed into a tablet or filled into an outer capsule or moulded intoan appropriate dosage form which can administered orally.

When administered the hydrocortisone preparation is administered inpharmaceutically acceptable preparations. Such preparations mayroutinely contain pharmaceutically acceptable diluents, carriers orprocessing aids such as inorganic salts, excipient fillers, bufferingagents, preservatives and compatible carriers.

Such amounts will depend, of course, on the particular condition beingtreated, the severity of the condition, the individual patientparameters including age, physical condition, size and weight, theduration of the treatment, the nature of concurrent therapy (if any),and like factors within the knowledge and expertise of the healthpractitioner. These factors are well known to those of ordinary skill inthe art and can be addressed with no more than routine experimentation.It is generally preferred that a maximum dose of the individualcomponents or combinations thereof be used, that is, the highest safedose according to sound medical judgment. The hydrocortisone preparationused contains an effective amount of drug for producing the desiredresponse in a unit of weight or volume suitable for administration to apatient.

The doses of hydrocortisone administered to a subject can be chosen inaccordance with different parameters, in particular the state of thesubject and also their weight. Other factors include the desired periodof treatment. In the event that a response in a subject is insufficientat the initial doses applied, higher doses (or effectively higher dosesby a different, more localized delivery route) may be employed to theextent that patient tolerance permits.

Administration of hydrocortisone preparations to mammals other thanhumans, (e.g. for testing purposes or veterinary therapeutic purposes),is carried out under substantially the same conditions as describedabove although dosages will vary in accordance with the size of theanimal treated. A subject, as used herein, is a mammal, preferably ahuman, and including a non-human primate, cow, horse, pig, sheep, goat,dog, cat or rodent.

When administered, the hydrocortisone preparation is administered inpharmaceutically-acceptable amounts and in pharmaceutically-acceptablecompositions. The term “pharmaceutically acceptable” means a non-toxicmaterial that does not interfere with the effectiveness of thebiological activity of the active ingredients. Such preparations mayroutinely contain salts, buffering agents, preservatives, compatiblecarriers, and optionally other therapeutic agents. When used inmedicine, the salts should be pharmaceutically acceptable, butnon-pharmaceutically acceptable salts may conveniently be used toprepare pharmaceutically-acceptable salts thereof and are not excludedfrom the scope of the invention. Such pharmacologically andpharmaceutically-acceptable salts include, but are not limited to, thoseprepared from the following acids: hydrochloric, hydrobromic, sulfuric,nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic,succinic, and the like. Also, pharmaceutically-acceptable salts can beprepared as alkaline metal or alkaline earth salts, such as sodium,potassium or calcium salts.

Hydrocortisone preparations may be combined, if desired, with apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier” as used herein means one or morecompatible solid or liquid fillers, diluents or encapsulating substanceswhich are suitable for administration into a human and are typicallyinert.

The term “carrier” denotes an organic or inorganic ingredient, naturalor synthetic, with which the active ingredient is combined to facilitatethe application. The components of the pharmaceutical compositions alsoare capable of being co-mingled with hydrocortisone, and with eachother, in a manner such that there is no interaction which wouldsubstantially impair the desired pharmaceutical efficacy.

The multi-particulate core matrix is combined with pharmaceuticallyacceptable excipients, which may include: (a) fillers such as lactose,manitose, dicalcium phosphate, microcrystalline cellulose, starch,pre-gelatanised starch, (b) binders such as hydroxypropyl cellulose,polyvinyl pyrrolidone, polyvinyl acetate, (c) powder flow enhancers suchcolloidal silicon dioxide (d) lubricants such as magnesium stearate,sodium stearyl fumarate (e) disintegrants such as sodium starchglycollate and polyvinyl pyrrolidone and (f) anti-sticking agents suchas talc.

The hydrocortisone preparation may contain suitable solubility enhancingand buffering agents. The hydrocortisone preparation also may contain,optionally, compatible preservatives or chemical and physicalstabilising agents known to those skilled in the art.

In an alternative preferred embodiment of the invention hydrocortisonemay be substituted for cortisone acetate.

According to a further aspect of the invention there is provided apharmaceutical composition according to the invention for use in thetreatment of adrenal dysfunction.

Preferably the adrenal dysfunction is caused by a condition selectedfrom the group consisting of: primary or secondary or tertiary adrenalfailure, congenital adrenal hyperplasia, late-onset congenital adrenalhyperplasia, polycystic ovarian failure, glucocorticoid-remediablealdosteronism (GRA).

In a preferred embodiment of the invention said condition is tertiaryadrenal insufficiency.

Tertiary adrenal insufficiency is adrenal insufficiency as a result ofprevious steroid treatment or Cushing's syndrome. For tertiary adrenalinsufficiency the treatment regimen can be for traditional adrenalinsufficiency but at the same time there may be a desire to wean thesubject off steroids and attempt a recovery of the pituitary adrenalaccess e.g. steroid withdrawal. In this situation the treatment regimenwould be to give a delayed formulation according to the invention atnight to reproduce the overnight secretion of cortisol and graduallywean down the dose to allow recovery of the pituitary adrenal access.This type of regimen could be applied to different indications forexample patients who had high dose steroids for some time forinflammatory disease such as rheumatoid arthritis or in cancer therapy.Typically, the treatment regimen would allow recovery from tertiaryadrenal insufficiency or partial suppression of the pituitary adrenalaccess.

In a preferred embodiment of the invention adrenal dysfunction is causedby congenital adrenal dysfunction.

In a preferred embodiment of the invention said composition isadministered at between 20:00 hrs and 24:00 hrs; preferably a secondcomposition is administered between 06:00 hr and 10:00 h.

According to an aspect of the invention there is provided a method totreat adrenal insufficiency in a subject that is deficient in adrenalcortisol secretion or has glucocorticoid-remediable aldosteronism (GRA),said method comprising or consisting of:

-   -   i) administering a first composition according to the invention        between 20:00 h and 24:00 h; and    -   ii) administering a second composition according to the        invention between 06:00 h and 10:00 h wherein the combination of        first and second compositions reproduce the normal circadian        rhythm of cortisol secretion thereby controlling adrenal        insufficiency in a physiological manner.

According to a further aspect of the invention there is provided atreatment regimen to treat adrenal insufficiency orglucocorticoid-remedial aldosteronism comprising or consisting ofproviding a first composition according to the invention to a subjectthat is suffering from adrenal insufficiency and administering saidfirst composition at between 20:00 h and 24:00 h; and providing a secondcomposition according to the invention and administering to said samesubject between 06:00 h and 10:00 h for use in the control of adrenalinsufficiency.

In a preferred method or use of the invention said first and secondcompositions comprise 1-60 mg of hydrocortisone; preferably about 5-40mg of hydrocortisone; preferably given two thirds at night and one thirdin the morning for example 50-70% in the evening and 30-50% in themorning.

In a preferred method or use of the invention adrenal insufficiency iscaused by a condition selected from the group consisting of: primary orsecondary or tertiary adrenal failure, congenital adrenal hyperplasia,late-onset congenital adrenal hyperplasia, polycystic ovarian failure orAddison's disease.

According to a further aspect of the invention there is provided apharmaceutical composition according to the invention for use in thetreatment of inflammatory diseases or conditions.

Preferably the inflammatory disease or condition is the result of anautoimmune disease.

There is a vast array of diseases exhibiting a chronic inflammatorycomponent. These include but are not limited to: inflammatory jointdiseases (e.g., rheumatoid arthritis, polymyalgia rheumatica (PMR)osteoarthritis, polyarthritis and gout), chronic inflammatory connectivetissue diseases (e.g., systemic lupus erythematosus, scleroderma,Sjorgen's syndrome, poly- and dermatomyositis, vasculitis, mixedconnective tissue disease (MCTD), tendonitis, synovitis, bacterialendocarditis, osteomyelitis and psoriasis); chronic inflammatory lungdiseases (e.g., asthma, chronic respiratory disease, pneumonia,fibrosing alveolitis, chronic bronchitis, chronic obstructive pulmonarydisease (COPD), bronchiectasis, emphysema, silicosis and otherpneumoconiosis and tuberculosis); chronic inflammatory bowel andgastro-intestinal tract inflammatory diseases (e.g., ulcerative colitisand Crohn's disease); chronic neural inflammatory diseases (e.g.,chronic inflammatory demyelinating polyradiculoneuropathy, chronicinflammatory demyelinating polyneuropathy, multiple sclerosis,Guillan-Barre Syndrome and myasthemia gravis); other inflammatorydiseases (e.g., mastitis, laminitis, laryngitis, chronic cholecystitis,Hashimoto's thyroiditis, inflammatory breast disease); chronicinflammation caused by an implanted foreign body in a wound; andincluding chronic inflammatory renal diseases including crescenticglomerulonephritis, lupus nephritis, ANCA-associated glomerulonephritis,focal and segmental necrotizing glomerulonephritis, IgA nephropathy,membranoproliferative glomerulonephritis, cryoglobulinaemia andtubulointerstitial nephritis. Diabetic nephropathy may also have achronic inflammatory component and chronic inflammatory responses areinvolved in the rejection of transplanted organs. It is apparent thatmany diseases have an inflammatory component many of which areautoimmune diseases.

In a preferred embodiment of the invention said inflammatory disease isrheumatoid arthritis or polymyalgia rheumatica.

In an alternative embodiment of the invention said inflammatory diseaseis inflammatory bowel disease.

In a preferred embodiment of the invention said inflammatory boweldisease is selected from the group consisting of: Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's colitis.

In a preferred embodiment of the invention said inflammatory boweldisease is Crohn's disease.

In a further preferred embodiment of the invention said inflammatorybowel disease is ulcerative colitis.

In a preferred embodiment of the invention said composition isadministered before sleep, for example between 20:00 hrs and 24:00 hrs.

According to an aspect of the invention there is provided a method totreat an inflammatory disease or condition in a subject that issuffering from said disease or condition, comprising or consisting ofadministering an effective amount of at least one composition accordingto the invention prior to sleep wherein said composition[s] does notsuppress the normal circadian rhythm of cortisol secretion and controlssaid inflammatory disease or condition.

In a preferred method of the invention said disease is rheumatoidarthritis.

In an alternative preferred method of the invention said disease isinflammatory bowel disease.

Preferably inflammatory bowel disease is Crohn's disease or ulcerativecolitis.

In a preferred method or use of the invention said first and secondcompositions comprise 1-60 mg of hydrocortisone; preferably about 5-40mg of hydrocortisone; most preferably 20-30 mg of hydrocortisone.

In a preferred method of the invention said composition according to theinvention is provided once nightly.

According to a further aspect of the invention there is provided apharmaceutical composition according to the invention wherein saidcomposition provides a delayed release of hydrocortisone to reset andre-entrain the circadian rhythm of cortisol in the treatment ofdepression or depression associated conditions.

Diseases or conditions that would benefit from entrainment of cortisolsecretion include but are not limited to, depression, sleep disorder,fatigue, abnormal eating, addiction, anxiety, immune response,inflammation, arthritis, asthma, jet lag.

In a preferred embodiment of the invention said use is the treatment ofdepression or a condition which results in depression, or similarcondition.

In a preferred embodiment of the invention the depression is clinicaldepression.

In a further preferred embodiment of the invention the depression isreactive depression.

In a still further preferred embodiment of the invention the depressionis post-natal depression.

In a further preferred embodiment of the invention said condition ormalaise is selected from the following group: chronic fatigue syndrome;myalgic encephalitis; jet lag; shift work, depression resulting from aperson being overweight; depression resulting from dieting; depressionresulting from the treatment of cigarette addiction; depressionresulting from the treatment of alcohol addiction; depression resultingfrom the treatment of drug addiction (e.g. cocaine, heroin); thetreatment of seasonal affective disorder or a like condition.

In a further preferred embodiment of the invention said conditionresults from the administration of an antipsycotic drug.

In a preferred method of the invention said antipsycotic drug isselected from the group consisting of: clozapine, olanzapine,risperidone, quetiapine or sertindole.

According to a further aspect of the invention there is provided aprocess for the manufacture of a delayed release hydrocortisoneformulation comprising the following steps:

-   -   i) forming a suspension comprising hydrocortisone and a binding        agent in an aqueous vehicle;    -   ii) providing a micro-particulate carrier;    -   iii) applying the hydrocortisone suspension to the        micro-particulate carrier to coat said carrier;    -   iv) drying the hydrocortisone coated micro-particulate carrier;    -   v) providing a colloidal solution comprising a delayed release        polymer wherein said delayed release polymer is a single or        blend of pH sensitive enteric polymer(s), a solvent or mixture        of solvents, an anti-tacking/flow agent and a plasticizer;    -   vi) applying the solution formed in (v) to the dried        micro-particulate carrier in vii); and optionally    -   viii) encapsulating the finished formulation in unit dosage        form.

In a preferred process of the invention the binding agent includesprovidone.

In a preferred process of the invention the micro-particulate carrier ismicrocrystalline cellulose or sugar beads.

In preferred process of the invention said blend of delayed releasepolymers comprises a mixture of Eudragit S100 and Eudragit L100.

Preferably the blend of Eudragit S100 and Eudragit L100 is in a ratio ofabout 4:1.

In a preferred process of the invention said plasticiser is dibutylsebacate.

In a preferred process of the invention said anti-tacking/flow agent istalc.

In a preferred method of the invention hydrocortisone and the bindingagent solution is applied as a spray.

In a preferred method of the invention process the delayed releasepolymer solution is applied as a spray.

According to a further aspect of the invention there is provided apharmaceutical formulation manufactured by a process according to theinvention.

In a preferred embodiment of the invention hydrocortisone is provided ata final concentration of between 2-10% w/w or 5-8% w/w or about 6% w/wof the composition formed by the process.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of the words, for example“comprising” and “comprises”, means “including but not limited to”, andis not intended to (and does not) exclude other moieties, additives,components, integers or steps.

Throughout the description and claims of this specification, thesingular encompasses the plural unless the context otherwise requires.In particular, where the indefinite article is used, the specificationis to be understood as contemplating plurality as well as singularity,unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith.

An embodiment of the invention will now be described by example only andwith reference to the following figures:

FIG. 1: illustrates the analysis of 24 hours circadian profile inhealthy volunteers;

FIG. 2A: illustrates the in vitro dissolution profile of a delayed andsustained release hydrocortisone formulation [DIURF-001] compared toFIG. 2B which illustrates a delayed release hydrocortisone formulation[DIURF-006];

FIG. 3: illustrates a pharmacokinetic comparison of a delayed andsustained release hydrocortisone formulation with a delayed releasehydrocortisone formulation; and

FIG. 4 is a delayed hydrocortisone profile compared to normal circadianprofile to illustrate the reproduction of the circadian release ofcortsol using a delayed formulation of hydrocortisone.

FIG. 5: The mean plasma concentration of hydrocortisone versus timeplots for Chronocort® administered in single doses of 5 mg, 10 mg and 20mg at night (23:00 h)

FIG. 6: The mean plasma concentration of hydrocortisone versus timeplots for Chronocort® administered in a cumulative dose of 30 mg, givenas 20 mg at night (23:00 h) and 10 mg in the morning (7:00 h).Comparison is made to the normative published data for cortisol (Debonoet al., 2009) and Hydrocortisone immediate release tablet (from studyDIUR-001).

FIG. 7: Comparison of exposure of hydrocortisone from Chronocort®formulation, in respect of area under the curve (AUC0-t) over the doserange 5 mg to 30 mg.

DEFINITIONS

“Controlled release” is the drug release profile delivered by a dosageform, usually via zero-order or first order, with the objective ofmaintaining a level of drug in the bloodstream which is invariant withtime over the dosing interval.

“Delayed release” is the drug release profile delivered by a dosage formwhich is characterised by an initial period of complete absence of drugrelease or very low drug release, typically less than or equal to 10% ofthe overall dose in the dosage form, prior to the main drug releasephase.

“Sustained release” is the drug release profile delivered by a dosageform, usually via first order or pseudo first order, with the objectiveof sustaining the duration of release such that the frequency of dosingis less than or equal to half that achieved with an immediate releasedosage form.

“Enteric polymer” is a homopolymer or copolymer or mixtures thereof thathave pH dependent solubility in aqueous media characterised generally bylow aqueous solubility under acidic conditions (pH1-4) and higheraqueous solubility under weakly acidic conditions and above (pH>5). Thepurpose is to protect the dosage from polymer dissolution mediatedrelease in the acidic gastric environment of the gut.

“Eudragit L100” is a defined mixture of polymethacrylates [CAS number:2506-15-1] with the chemical composition: poly(methacrylic acid, methylmethacrylate) in a ratio of 1:1.

“Eudragit S100” is a defined mixture of polymethacrylates [CAS number:25086-15-1] with the chemical composition: poly(methacrylic acid, methylmethacrylate) in a ratio of 1:2.

The terms “multi-particulate” and “micro-particulate” are to be usedinterchangeably and are equivalent to one another in form and function.

Materials and Methods

Method of Manufacture

The manufacturing process for Formulation DIURF-001 involves steps 1-4

The manufacturing process for Formulation DIURF-006 involves steps 1, 3and 4 only.

Process Step 1: Description of the Preparation of the HydrocortisoneCoated Cellets®

-   -   Weigh out the required materials in the relevant quantities.    -   Add the Povidone to the water and mix using an overhead stirrer        for approximately 5 minutes.    -   To the Povidone solution add the hydrocortisone and homogenise        using an appropriate homogeneiser. Mix until homogenous        (approximately 30 minutes).    -   Remove the homogeniser and replace with an overhead stirrer.        Ensure the suspension is mixed throughout the spray process.    -   Set up the Fluid Bed Drier (example: Glatt GPCG3) with the        Wurster attachment and retaining basket.    -   Place the Cellets® into the Fluid Bed Drier and fluidise until a        product temperature of above 20° C. is reached.    -   Set the Wurster attachment to 25 mm height whilst the Cellets®        are fluidised.    -   Spray on the API solution using the following parameters:—        -   Atomising air=˜1.8 bar        -   Filter Shaker=15 seconds every 30 seconds        -   Inlet air temperature=40° C.        -   Inlet air volume=60 m³/sec        -   Pump Speed=˜15 g/min (for first 30 minutes), ˜18 g/min            thereafter.        -   [Use: 400 μm retaining basket for the above operation]    -   Determine the end-point by the amount of suspension sprayed onto        the batch by weight.    -   After the spraying process has finished the hydrocortisone        coated Cellets® are kept fluidised for 30 minutes to allow them        to dry sufficiently.    -   Sieve the hydrocortisone coated Cellets® through a 1.4 mm sieve,        this will remove any agglomerates.

Process Step 2: Description of the Sustained Release Coating

-   -   Weigh out the required materials in the relevant quantities.    -   Mix together the isopropanol, acetone, Eudragit RL100/RS100        using an overhead stirrer at a speed enough to create a vortex        but without overspill. Mix until a solution is obtained.    -   Add the dibutyl sebacate, purified water and talc to the        solution and continue mixing throughout the coating process to        keep the talc suspended.    -   Set up the Fluid Bed Drier with Wurster attachment and retaining        basket.    -   Place the hydrocortisone coated Cellets® (from Unit process 1)        into the Fluid Bed Drier and fluidise until a product        temperature of between 20° C. and 25° C. is reached.    -   Set the Wurster attachment to 25 mm height whilst the        hydrocortisone coated Cellets® are fluidised.    -   Spray on the polymer suspension using the following parameters:        —        -   Atomising air=˜1.8 bar        -   Filter Shaker=15 seconds every 30 seconds        -   Inlet air temperature=25° C.        -   Inlet air volume=60 m³/sec        -   Pump Speed=˜15 g/min (for first 30 minutes), ˜18 g/min            thereafter.        -   [Use: 400 μm retaining basket for the above operation]    -   Determine the end-point by the amount of suspension sprayed onto        the batch by weight.    -   Once the end point has been reached stop spraying the suspension        and remove the hydrocortisone sustained release coated Cellets®        from the Fluid Bed Drier.    -   Sieve the hydrocortisone sustained release coated Cellets®        through a 1.4 mm sieve, this will remove any agglomerates.    -   Add approximately 1% weight of talc to the hydrocortisone        sustained release coated Cellets® to reduce the possibility of        any sticking.        Process Step 3: Description of the enteric (delayed release)        coating    -   Weigh out the required materials in the relevant quantities.    -   Mix together the isopropanol, acetone, Eudragit S100 and L100        using an overhead stirrer at a speed enough to create a vortex        but without overspill. Mix until a solution is obtained.    -   Add the dibutyl sebacate, water and talc to the solution and        continue mixing throughout the coating process to keep the talc        suspended.    -   Set up the Fluid Bed Drier with Wurster attachment and retaining        basket.    -   Place the hydrocortisone sustained release coated Cellets® into        the Fluid Bed Drier and fluidise until a product temperature of        between 20° C. and 25° C. is reached.    -   Set the Wurster attachment to 25 mm height whilst the        hydrocortisone sustained release coated Cellets® are fluidised.    -   Spray on the polymer suspension using the following parameters:—        -   Atomising air=˜1.8 bar        -   Filter Shaker=15 seconds every 30 seconds        -   Inlet air temperature=25° C.        -   Inlet air volume=60 m³/sec        -   Pump Speed=˜15 g/min (for first 30 minutes), ˜18 g/min            thereafter.        -   [Use: 400 μm retaining basket for the above operation]    -   Determine the end-point by the amount of suspension sprayed onto        the batch by weight.    -   Once the end point has been reached stop spraying the suspension        and remove the Hydrocortisone sustained and delayed release        coated Cellets® from the Fluid Bed Drier.    -   Sieve the hydrocortisone delayed and sustained release coated        Cellets® through a 1.4 mm sieve, this will remove any        agglomerates.    -   Add approximately 1% weight of talc to the hydrocortisone        delayed and sustained release coated Cellets® to reduce the        possibility of any sticking.

Process Step 4: Description of the Encapsulation, Bulk Packaging andLabelling

-   -   Set up the encapsulation machine.    -   Fill hopper with the hydrocortisone delayed and sustained        release coated Cellets® (from Unit process 3).    -   Fill capsule holder with the empty size 00 capsule shells.

Set machine to fill at the required fill weight.

Dissolution Methodology

Dissolution testing of Hydrocortisone Controlled Releasemulti-particulates was conducted using USP Apparatus I (Baskets), with atotal of 900 mL of dissolution media, involving two subsequentsequential media changes, and a basket speed of 100 rpm. Dissolution wasconducted initially in 700 mL of simulated gastric fluid (USP, pH 1.2)for 2 hours, followed by further dissolution in 850 mL of media adjustedto pH 6.0 (via the addition of pre-warmed 150 mL of 0.18 M trisodiumortho phosphate dodecahydrate buffer) for 1 hour, and then dissolutionin 900 mL of media adjusted to pH 7.2 (via the addition of pre-warmed 50mL of 0.23 M trisodium ortho phosphate dodecahydrate buffer).

Assay of Hydrocortisone

The concentration of Hydrocortisone in the multi-particulates andreleased during the dissolution evaluation was determined using thefollowing method. The hydrocortisone solution was diluted in the mobilephase solution comprising tetrahydrofuran/water (20:80 v/v). Theresulting solution was into a HPLC, set-up with a Phenomenex Luna columnC18(2), 5 μm, 150 mm×4.6 mm, equilibrated at 45° C. The samples were runusing Isocratic conditions employing tetrahydrofuran/water (20:80 v/v)as the mobile phase at a flow rate of 1.5 mL/minute. Detection is by UVat a wavelength of 254 nm.

Example 1

The circadian secretion of cortisol in human subjects was analyzed inhealthy volunteers. The measurement of cortisol was by liquidchromatography-mass spectrometry (LC-MS). The geometric mean (blackline) of the cortisol levels was calculated; see FIG. 1. The top greyline is the 90^(th) centile for geometric mean and the bottom grey lineis the 10^(th) centile for the geometric mean. Samples were obtained at20 min intervals. The 24 h cortisol profiles in 28 healthy volunteerswere measured using a Waters Xevo mass spectrometer with Acquity uPLCsystem (limit of quantitation 0.01 μg/dl or 0.3 nmol/l, and relativestandard deviation <15% at low and <10% at medium and high cortisollevels). The circadian rhythm of cortisol secretion is clearly shownwith a peak level between 06:00 to 09:00 h with maintenance of cortisollevels above 100 nmol/l until approximately 19:00 h; see FIG. 1.

Example 2

FIG. 2 illustrates the in vitro dissolution of a delayed and sustainedrelease hydrocortisone formulation with a delayed release formulation.FIG. 2A shows an approximate 3-hour delayed period prior to the onset ofdrug release followed by a sustained drug release phase of c. 8-10hours. In contrast, in FIG. 2B the in vitro dissolution profile of adelayed release hydrocortisone formulation shows a similar 3-hourdelayed period prior to the onset of drug release which is followed byan immediate release of hydrocortisone.

Example 3

An in vivo pharmacokinetic comparison in healthy human volunteers (n=6)of 30 mg delayed only hydrocortisone formulation compared to a 30 mgdelayed-sustained hydrocortisone formulation is illustrated in FIG. 3.The analysis was conducted by LC-MS and comparison is made to the normalcircadian cortisol profile already shown in FIG. 1. The comparison isillustrated below:

Normals:

-   -   AUC/Bioavailability=4697 nM·hr    -   Cmax=451.5 nMol/l    -   Tmax=07:52 h

Delayed Release Formulation:

-   -   AUC/Bioavailability of delayed=4595 nm·hr (98% compared to        normals)    -   Cmax=507.0 nMol/l    -   Tmax=08:00 h

Delayed-Sustained Release Formulation:

-   -   AUC/Bioavailability=1628 nM·hr (35% compared to Normals)    -   Cmax=159 nMol/l    -   Tmax=05:00 h

The delayed release hydrocortisone formulation has a greater Cmax, alater Tmax and greater AUC than the delayed and sustained formulation.These results are unexpected based on the in vitro dissolution datashown in FIGS. 2A and 2B and in the prior art which teaches theprovision of a delayed and sustained release formulation is required toprovide hydrocortisone formulations with the requisite release profileto reproduce the circadian rhythm of cortisol secretion. It would bepredicted that a delayed only formulation would generate an earlier Cmaxand an un-sustained absorption profile compared to a delayed andsustained formulation. However, in vivo, in humans, the delayed onlyformulation has a later Tmax, a more sustained absorption and greaterAUC than the delayed-sustained formulation and replicates the normalovernight cortisol profile. This is graphically represented in FIG. 4which shows the geometric mean and 10^(th) and 90^(th) centile cortisollevels for a 30 mg delayed formulation overlaid on the normal cortisollevels again shown as geometric mean and 10^(th) and 90^(th) centile.

Example 4

An open label, randomised, single dose, crossover study was conducted in28 healthy volunteers to characterize the pharmacokinetics ofChronocort® (Formulation DIURF-006) to demonstrate the closeness of fitto the physiological circadian rhythm of cortisol. Healthy volunteerswere screened and enrolled onto the study. The principal inclusioncriteria were healthy male subjects between the ages of 18 and 60 years,who did not work shifts and who had no clinically significant systemicinfections and/or history of allergy/sensitivity tohydrocortisone/dexamethasone. Each subject received Chronocort®(Formulation DIURF-006) on four occasions seperated by a one-weekwashout period. On each occasion the dose of Chronocort® administeredwas one of the following: 5 mg, 10 mg or 20 mg (given at 23:00 h) or 30mg (given as 20 mg at 23:00 h and 10 mg at 7:00 h the following day).Prior to each administration of Chronocort® each subject was dosed withdexamethasone (1 mg at approximately 4-6 hourly intervals) to supressendogenous release of cortisol. Pharmacokinetic sampling was conductedat defined time-points over a course of 24-hour after each Chronocort®dosing.

The plasma concentration of hydrocortisone was determined using avalidated high-pressure liquid chromatography mass spectrometry (LC-MS)assay. The analysis of pharmacokinetic parameters was conducted usingWinNonlin Professional (version 5.2.1). Comparison of thepharmacokinetic profile for Chronocort® was made in relation tohydrocortisone immediate release tablet (historical in-house data fromstudy DIUR-001) and reference normative cortisol profile of healthyindividuals (published by Debono et al., 2009).

The pharmacokinetic profiles for Chronocort® administered insingle-doses of 5 mg, 10 mg and 20 mg (at 23:00 h) are shown in FIG. 5.All profiles show a characteristic period of delayed release for theinitial 2-4 hours post-dosing followed by a gradual rise in plasmaconcentration attaining a maximal concentration (Cmax) typically around7-hours post dosing.

The pharmacokinetic profile for Chronocort® administered in a cumulativedose of 30 mg (20 mg at 23:00 h and 10 mg at 7:00 h) is shown in FIG. 6.The closeness of fit to the normative circadian profile of cortisol inhealthy individuals is compared in the same plot. The referencepharmacokinetic profile for hydrocortisone immediate release tablet isalso represented to illustrate the marked improvement in the closenessof fit of Chronocort® to the normative cortisol profile in comparison toconventional Hydrocortisone immediate release formulation.

The proportionality of exposure of hydrocortisone from Chronocort® atdifferent doses is shown in FIG. 7. It can be noted that between thedose range of 5 mg to 30 mg, the exposure of hydrocortisone from theChronocort® formulation is essentially linear.

TABLE 1 Delayed Release Formulation [DIURF-006] Hydrocortisone ModifiedRelease Capsule formulation, dose strengths: 5 mg, 10 mg, 20 mg and 30mg Quantity (mg/capsule) Quantity DIURF-006 5 mg mg 20 mg 30 mg (%Ingredient Grade Function Capsule Capsule Capsule Capsule w/w)Microcrystalline cellulose Ph. Eur./USP Inert core 66.76 133.51 267.01400.52 81.36 spheres (Cellets ® 500) and supplier specificationHydrocortisone USP Ph. Eur./USP Active agent 5.00 10.00 20.00 30.00 6.09Micronized EP Water for Injection Ph. Eur./USP Coating Solvent (93.63)(187.25) (374.49) (561.74) — Povidone (Kollidon 25) Ph. Eur. Binder 1.513.01 6.02 9.03 1.83 Delayed release coat Isopropanol Alcohol BP CoatingSolvent (46.46) (92.92) (185.83) (278.75) — Acetone BP Coating Solvent(30.97) (61.95) (123.89) (185.84) — Water for Injection Ph. Eur./USPCoating Solvent (3.10) (6.20) (12.39) (18.59) — Eudragit S100 Ph.Eur./NF Coating Polymer 4.40 8.81 17.61 26.42 5.37 Eudragit L100 Ph.Eur./NF Coating Polymer 1.10 2.20 4.40 6.60 1.34 Talc¹ BP/NFAnti-sticking 2.74 5.49 10.97 16.46 3.34 agent Dibutyl Sebacate NFPlasticiser 0.55 1.09 2.18 3.27 0.67 Talc² BP/NF Anti-sticking (0.82)(1.64) (3.28) (4.92) — agent Total 82.06 164.11 328.19 492.30 100.0 ()—Removed during processing, does not appear in the final product,required quantity shown in parenthesis ¹Talc included in the coatingformulation as anti-sticking agent ²Talc included extra-granularly asanti-sticking agent and is removed in the manufacturing process

TABLE 2 Delayed and Sustained Release Formulation [DIURF-001]Hydrocortisone Modified Release Capsule formulation, dose strengths: 5mg, 10 mg and 20 mg Quantity (mg/capsule) Quantity 5 mg 10 mg 20 mg (%Ingredient Grade Function Capsule Capsule Capsule w/w) MicrocrystallinePh. Eur./USP Inert core 66.67 133.34 266.68 56.06 cellulose spheres andsupplier (Cellets ® 500) specification Hydrocortisone USP Ph. Eur./USPActive agent 5.00 10.00 20.00 4.20 Micronized EP Water for Injection Ph.Eur./USP Coating Solvent (93.50) (187.00) (374.00) — Povidone (Kollidon25) Ph. Eur. Binder 1.50 3.00 6.00 1.26 Sustained release coatIsopropanol Alcohol BP Coating Solvent (96.03) (192.06) (384.12) —Acetone BP Coating Solvent (64.02) (128.04) (256.08) — Water forInjection Ph. Eur./USP Coating Solvent (6.40) (12.80) (25.60) — EudragitRS100 Ph. Eur./NF Coating Polymer 4.57 9.14 18.28 3.84 Eudragit RL100Ph. Eur./NF Coating Polymer 6.86 13.72 27.44 5.77 Talc¹ BP/NFAnti-sticking agent 5.72 11.44 22.88 4.81 Dibutyl Sebacate NFPlasticiser 1.14 2.28 4.56 0.96 Talc² BP/NF Anti-sticking agent (1.19)(2.38) (4.76) — Delayed release coat Isopropanol Alcohol BP CoatingSolvent (102.94) (205.88) (411.75) — Acetone BP Coating Solvent (68.63)(137.26) (274.52) — Water for Injection Ph. Eur./USP Coating Solvent(6.86) (13.72) (27.44) — Eudragit S100 Ph. Eur./NF Coating Polymer 13.7327.46 54.92 11.55 Eudragit L100 Ph. Eur./NF Coating Polymer 3.43 6.8613.72 2.88 Talc¹ BP/NF Anti-sticking agent 8.58 17.16 34.32 7.22 DibutylSebacate NF Plasticiser 1.72 3.44 6.88 1.45 Talc² BP/NF Anti-stickingagent (1.19) (2.38) (4.76) — Total 118.92 237.84 475.68 100.00 ()—Removed during processing, does not appear in the final product,required quantity shown in parenthesis ¹Talc included in the coatingformulation as anti-sticking agent ²Talc included extra-granularly asanti-sticking agent and is removed in the manufacturing process

1. A pharmaceutical composition adapted for oral administrationcomprising: a core comprising hydrocortisone and a carrier andcontacting said core a layer comprising a delayed release polymerwherein said delayed release polymer is a single or blend of pHsensitive enteric polymer(s) and is adapted to delay release ofhydrocortisone from said core characterized in that the carriercomprises microcrystalline cellulose which is 75-85% w/w of thecomposition.
 2. The composition according to claim 1, wherein saidmicrocrystalline cellulose particles have a diameter of 200 μm to 1200μm.
 3. The composition according to claim 2, wherein the diameter ofsaid particles is 500 μm to 800 μm.
 4. The composition according toclaim 1, wherein said composition comprises 80-82% w/w microcrystallinecellulose.
 5. The composition according to claim 4, wherein saidcomposition comprises 81% w/w microcrystalline cellulose.
 6. Thecomposition according to claim 1, wherein the hydrocortisone is 2-10%w/w of the composition.
 7. The composition according to claim 6, whereinthe concentration of hydrocortisone is 5-8% w/w of the composition. 8.The composition according to claim 6, wherein the concentration ofhydrocortisone is 6% w/w of the composition.
 9. The compositionaccording to claim 1, wherein the hydrocortisone is present in or on thesaid core together with a binding agent.
 10. The composition accordingto claim 9, wherein the binding agent is providone at a concentration of0.5-4.0% w/w of the composition.
 11. The composition according to claim10, wherein the concentration of povidone is 1.5-3.0% w/w of thecomposition.
 12. The composition according to claim 11, wherein thepovidone is at a concentration of 1.8% w/w of the composition.
 13. Thecomposition according to claim 1, wherein dissolution of saidcomposition is pH 5.5 to 7.0.
 14. The composition according to claim 13,wherein said enteric polymer[s] is acrylic and/or poly [methyl] acrylicpolymers, cellulose acetate succinate or polyvinylacetate phathlate. 15.The composition according to claim 14, wherein said enteric polymers areammonio methacrylate copolymers.
 16. The composition according to claim15, wherein said enteric polymer[s] is a methacrylic acid derivative.17. The composition according to claim 16, wherein said enteric polymerscomprises a mixture of Eudragit S100 poly [methacrylic acid, methylmethacrylate) in a ratio of 1:2] and Eudragit L100 [poly (methacrylicacid, methyl methacrylate) in a ratio of 1:1].
 18. The compositionaccording to claim 17, wherein the ratio of Eudragit S100 and EudragitL100 is 4:1.
 19. The composition according to claim 13, wherein saidenteric polymer[s] is 5-10% w/w of the composition.
 20. The compositionaccording to claim 19, wherein said enteric polymer[s] is 6-8% w/w ofthe composition.
 21. The composition according to claim 20, wherein saidenteric polymer[s] is 7% w/w of the composition.
 22. The compositionaccording to claim 21, wherein the enteric polymer layer comprises aplasticiser.
 23. The composition according to claim 22, wherein saidplasticiser comprises dibutyl sebacate.
 24. The composition according toclaim 23, wherein the dibutyl sebacate in said enteric polymer layer is0.5-1.0% w/w of the composition.
 25. The composition according to claim24, wherein the dibutyl sebacate in said enteric polymer layer is 0.7%w/w of the composition.
 26. A pharmaceutical composition adapted fororal administration comprising: a core comprising hydrocortisone and acarrier; and a layer comprising a delayed release polymer that contactssaid core, wherein said delayed release polymer is a pH sensitiveenteric polymer which is a mixture of poly (methacrylic acid, methylmethacrylate) in a ratio of 1:1 and poly (methacrylic acid, methylmethacrylate) in a ratio of 1:2 [1:4] at 6-7% w/w of the composition,which is adapted to delay release of hydrocortisone from said core. 27.The composition according to claim 26 wherein said compositioncomprises: 81% w/w microcrystalline cellulose spheres; 6.09% w/whydrocortisone; 1.83% w/w povidine; 5.37% w/w poly (methacrylic acid,methyl methacrylate) in a ratio of 1:2; 1.34% w/w poly (methacrylicacid, methyl methacrylate) in a ratio of 1:1; 3.34% talc; and 0.67%dibutyl sebacate. 28.-32. (canceled)
 33. A method to treat adrenalinsufficiency in a subject that is deficient in adrenal cortisolsecretion or has glucocorticoid-remediable aldosteronism (GRA), saidmethod comprising: i) administering a first dose of the composition ofclaim 1 between 20:00 h and 24:00 h; and ii) administering a second doseof the composition of claim 1 between 06:00 h and 10:00 h, wherein thecombination of the administrations reproduce the normal circadian rhythmof cortisol secretion thereby treating the adrenal insufficiency. 34.(canceled)
 35. The method of claim 33, wherein the first dose of thecomposition comprises about 20 mg hydrocortisone and the second dose ofthe composition comprises about 10 mg hydrocortisone.
 36. The methodaccording to claim 33, wherein the first dose of the composition isadministered at about 23:00 hr and the second dose of the composition isadministered at about 07:00 hr.
 37. The method of claim 33, wherein theadrenal insufficiency is caused by a primary or secondary or tertiaryadrenal failure, congenital adrenal hyperplasia, late-onset congenitaladrenal hyperplasia, polycystic ovarian failure, or Addison's disease.38. (canceled)
 39. The method according to claim 44, wherein theinflammatory disease or condition is the result of an autoimmunedisease.
 40. The method according to claim 39, wherein said inflammatorydisease is rheumatoid arthritis, polymyalgia rheumatic, or inflammatorybowel disease.
 41. (canceled)
 42. The method according to claim 40,wherein said inflammatory bowel disease is Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, or Behcet's colitis.
 43. (canceled)
 44. A method totreat an inflammatory disease or condition in a subject, comprisingadministering an effective amount of at least one composition accordingto claim 1 prior to sleep, wherein said composition[s] does not suppressthe normal circadian rhythm of cortisol secretion and treats saidinflammatory disease or condition.
 45. The method of claim 44, whereinsaid composition comprises 1-60 mg of hydrocortisone.
 46. The method ofclaim 44, wherein said composition is provided once nightly.
 47. Amethod of treating depression or a depression associated condition,comprising: administering an effective amount of the pharmaceuticalcomposition according to claim 1, wherein said composition provides adelayed release of hydrocortisone to reset and re-entrain the circadianrhythm of cortisol, thereby treating the depression or depressionassociated condition.
 48. The method according to claim 47, wherein thedepression is clinical depression, reactive depression, or post-nataldepression. 49.-50. (canceled)
 51. The method according to claim 47,wherein said depression associated condition is chronic fatiguesyndrome; myalgic encephalitis; jet lag; shift work, depressionresulting from a person being overweight; depression resulting fromdieting; depression resulting from the treatment of cigarette addiction;depression resulting from the treatment of alcohol addiction; depressionresulting from the treatment of drug addiction; or seasonal affectivedisorder.
 52. The method according to claim 47, wherein said depressionassociated condition results from the administration of an antipsycoticdrug.
 53. The method according to claim 52 wherein said antipsycoticdrug is clozapine, olanzapine, risperidone, quetiapine or sertindole.54.-64. (canceled)